In the initial stages of prostate cancer, growth of the tumor is sensitive to androgen ablation therapy. However, in many cases, the tumor progresses to an androgen-independent state for which there is no known therapy. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases (RTK) has often been implicated in the development of the androgen-independent phenotype. While HER1 and HER2 have been widely studied in prostate cancer, the role of HER3 is relatively unknown. In this application we propose to investigate the role of HER3 in the development of an androgen-independent phenotype. Preliminary data show that androgen independent prostate tumor cell lines overexpress HER3 and show increased activation of Akt compared to androgen-dependent cells. In addition, we made the novel observation that androgen independent cell lines expressed greater levels of HER1/HER3 heterodimers compared to androgen dependent cells. Overexpression of HER3 in an androgen dependent cell line induced increased proliferation and androgen-independence. We hypothesize that overexpression of HER3 in prostate cancer induces the formation of HER1/HER3 heterodimers, which results in androgen independence mediated by Akt. Based on this hypothesis, we propose the following: [unreadable] Aim 1. To determine if androgen-independence is a result of HER3 overexpression. We will investigate whether HER3 regulates androgen-dependence and induces androgen receptor transactivation. Also, in a retrospective immunohistochemical study using paraffin-embedded tissues we will examine whether HER3 expression correlates with increased proliferation and a poor clinical outcome in human prostate tumors. [unreadable] Aim 2. To elucidate the role of HER3 overexpression in the induction of the androgen-independent phenotype. We will evaluate the contribution of HER3 overexpression to increased Akt phosphorylation and investigate the role of HER1/HER3 heterodimerization in HER3-induced androgen independence. [unreadable] [unreadable] [unreadable]